Blood–Brain Barrier Disruption in Humans Is Independently Associated With Increased Matrix Metalloproteinase-9

Abstract

Background and Purpose-Matrix metalloproteinases (MMP) may play a role in blood-brain barrier (BBB) disruption after ischemic stroke. We hypothesized that plasma concentrations of MMP-9 are associated with a marker of BBB disruption in patients evaluated for acute stroke. Methods-Patients underwent MRI on presentation and Ϸ24 hours later. The MRI marker, termed hyperintense acute reperfusion injury marker (HARM), is gadolinium enhancement of cerebrospinal fluid on fluid-attenuated inversion recovery MRI. Plasma MMP-9 and tissue inhibitor of matrix metalloproteinase-1 were measured by enzyme-linked immunosorbent assay. Logistic regression models tested for predictors of HARM on 24-hour follow-up scans separately for MMP-9 and the ratio of MMP-9 to TIMP-1. Results-For the 41 patients enrolled, diagnoses were: acute ischemic cerebrovascular syndrome, 33 (80.6%); intracerebral hemorrhage, 6 (14.6%); stroke mimic, 1 (2.4%); and no stroke, 1 (2.4%). HARM was present in 17 (41.5%) patients. In model 1, HARM was associated with baseline plasma MMP-9 concentration (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.001-1.019; Pϭ0.033). In model 2, HARM was associated with the ratio of MMP-9 to tissue inhibitor of matrix metalloproteinase-1 (OR, 4.94; 95% CI, 1.27-19.14; Pϭ0.021). Conclusions-Baseline MMP-9 was a significant predictor of HARM at 24-hour follow-up, supporting the hypothesis that MMP-9 is associated with BBB disruption. If the association between MMP-9 and BBB disruption is confirmed in future studies, HARM may be a useful imaging marker to evaluate MMP-9 inhibition in ischemic stroke and other populations with BBB disruption. (Stroke. 2010;41:e123-e128.)

Fingolimod alters inflammatory mediators and vascular permeability in intracerebral hemorrhage

“…CET1-WI has been used routinely in cerebral stroke studies [24] ; the presence of parenchymal enhancement on CET1-WI is generally accepted as an indicator of contrast medium leakage across the disrupted BBB. The timeline for BBB disruption has been shown to include initiation on day 1, a peak on days 5-7, and can last 14 days or longer [25,26] . Therefore, here we evaluated the microvascular permeability on day 7.…”

Propofol post-conditioning protects the blood brain barrier by decreasing matrix metalloproteinase-9 and aquaporin-4 expression and improves the neurobehavioral outcome in a rat model of focal cerebral ischemia-reperfusion injury

“…MMP-9 is involved in the pathophysiological process of cerebral ischemia via the degradation of tight junctions between the basal lamina and endothelial cells, which results in the destruction of the BBB (16). MMP-9 has a pivotal role in BBB proteolysis (17), and increased MMP-9 expression and activation increases the permeability of the BBB and may therefore exacerbate cephaloedema (3,18,19). Furthermore, during cerebral ischemia hypoxia-inducible factor-1α may damage the BBB by activating the expression of AQP-4 and MMP-9 and aggravating cerebral edema.…”

Blood Biomarkers of Ischemic Stroke

“…Hyperglycemia and diabetes have also been associated with elevated MMP-9 and the development of hemorrhagic transformation [81]. {Uemura, 2001 #2927 BBB disruption independently correlates with serum MMP9 levels [82].…”